Gastric development of pancreatic acinar cell metaplasia after Vonoprazan therapy in rats.

BACKGROUND: Vonoprazan is a new acid-suppressing drug that received FDA approval in 2022. It reversibly inhibits gastric acid secretion by competing with the potassium ions on the luminal surface of the parietal cells (potassium-competitive acid blockers or P-CABs). Vonoprazan has been on the market for a short time and there are many clinical trials to support its clinical application. However, medical experience and comprehensive clinical data is still limited, especially on how and if, gastric histology is altered due to therapy. METHODS: A 12-week experiment trial with 30 Wistar rats was to assess the presence of gastrointestinal morphologic abnormalities upon administration of omeprazole and vonoprazan. At six weeks of age, rats were randomly assigned to one of 5 groups: (1) saline as negative control group, (2) oral omeprazole (40 mg/kg), as positive control group, (3) oral omeprazole (40 mg/kg) for 4 weeks, proceeded by 8 weeks off omeprazole, (4) oral vonoprazan (4 mg/kg), as positive control group, and (5) oral vonoprazan (4 mg/kg) for 4 weeks, proceeded by 8 weeks off vonoprazan. RESULTS: We identified non-inflammatory alterations characterized by parietal (oxyntic) cell loss and chief (zymogen) cell hyperplasia and replacement by pancreatic acinar cell metaplasia (PACM). No significant abnormalities were identified in any other tissues in the hepatobiliary and gastrointestinal tracts. CONCLUSION: PACM has been reported in gastric mucosa, at the esophagogastric junction, at the distal esophagus, and in Barrett esophagus. However, the pathogenesis of this entity is still unclear. Whereas some authors have suggested that PACM is an acquired process others have raised the possibility of PACM being congenital in nature. Our results suggest that the duration of vonoprazan administration at a dose of 4 mg/kg plays an important role in the development of PACM.

Long-term potassium-competitive acid blockers administration causes microbiota changes in rats.

BACKGROUND: Vonoprazan is a new potassium-competitive acid blocker (P-CAB) that was recently approved by the FDA. It is associated with a fast onset of action and a longer acid inhibition time. Vonoprazan-containing therapy for helicobacter pylori eradication is highly effective and several studies have demonstrated that a vonoprazan-antibiotic regimen affects gut microbiota. However, the impact of vonoprazan alone on gut microbiota is still unclear.Please check and confirm the authors (Maria Cristina Riascos, Hala Al Asadi) given name and family name are correct. Also, kindly confirm the details in the metadata are correct.Yes they are correct.  METHODS: We conducted a prospective randomized 12-week experimental trial with 18 Wistar rats. Rats were randomly assigned to one of 3 groups: (1) drinking water as negative control group, (2) oral vonoprazan (4 mg/kg) for 12 weeks, and (3) oral vonoprazan (4 mg/kg) for 4 weeks, followed by 8 weeks off vonoprazan. To investigate gut microbiota, we carried out a metagenomic shotgun sequencing of fecal samples at week 0 and week 12.Please confirm the inserted city and country name is correct for affiliation 2.Yes it's correct. RESULTS: For alpha diversity metrics at week 12, both long and short vonoprazan groups had lower Pielou's evenness index than the control group (p = 0.019); however, observed operational taxonomic units (p = 0.332) and Shannon's diversity index (p = 0.070) were not statistically different between groups. Beta diversity was significantly different in the three groups, using Bray-Curtis (p = 0.003) and Jaccard distances (p = 0.002). At week 12, differences in relative abundance were observed at all levels. At phylum level, short vonoprazan group had less of Actinobacteria (log fold change = - 1.88, adjusted p-value = 0.048) and Verrucomicrobia (lfc = - 1.76, p = 0.009).Please check and confirm that the author (Ileana Miranda) and their respective affiliation 3 details have been correctly identified and amend if necessary.Yes it's correct. At the genus level, long vonoprazan group had more Bacteroidales (lfc = 5.01, p = 0.021) and Prevotella (lfc = 7.79, p = 0.001). At family level, long vonoprazan group had more Lactobacillaceae (lfc = 0.97, p = 0.001), Prevotellaceae (lfc = 8.01, p < 0.001), and less Erysipelotrichaceae (lfc = - 2.9, p = 0.029). CONCLUSION: This study provides evidence that vonoprazan impacts the gut microbiota and permits a precise delineation of the composition and relative abundance of the bacteria at all different taxonomic levels.

Comparative Outcomes of Anti-Reflux Surgery in Obese Patients with Gastroesophageal Reflux Disease1.

INTRODUCTION: Roux-en-Y gastric bypass (RYGB) has been the preferred operation for obese patients with gastroesophageal reflux disease (GERD); however, some patients are hesitant to undergo bypass. Obese patients have a multifactorial predisposition to GERD, including lower esophageal sphincter (LES) dysfunction and aberrant pressure gradients across their diaphragmatic crura. Among non-obese patients, anti-reflux surgery (ARS) with hiatal hernia (HH) repair and LES augmentation has shown excellent long-term results. We aimed to determine whether patient satisfaction and GERD recurrence differed between obese and non-obese patients who underwent ARS. METHODS: Review of patients who underwent ARS between January 2012 and June 2021 was performed. Perioperative and postoperative characteristics were compared across three BMI groups: BMI < 30 kg/m2, 30 kg/m2 ≤ BMI < 35 kg/m2, and BMI ≥ 35 kg/m2. RESULTS: Four-hundred thirteen patients were identified, of which 294 (71.1%) had BMI < 30 kg/m2, 87 (21.1%) were 30 kg/m2 ≤ BMI < 35 kg/m2, and 32 (7.7%) had a BMI ≥ 35 kg/m2. Patients with BMI ≥ 35 kg/m2 had higher preoperative manometric and EndoFLIP™ intra-balloon pressure at the LES than those with lower BMIs. This value was increased to a similar level throughout ARS across the three cohorts. Post-operative GERD-specific satisfaction was similar across the three cohorts, as were rates of postoperative reflux and hiatal hernia recurrence on barium swallow; rates of reoperation were low. CONCLUSIONS: ARS with HH repair and LES augmentation may be appropriate for select patients across a range of BMIs, including those with a BMI ≥ 35 kg/m2 who are hesitant to undergo RYGB.

Quantifying physiologic parameters of the gastroesophageal junction during robotic sleeve gastrectomy and identifying predictors of post-sleeve gastroesophageal reflux disease.

BACKGROUND: Sleeve gastrectomy is among the most commonly-performed procedures for morbid obesity. However, patients occasionally develop post-sleeve gastroesophageal reflux disease (GERD). Identifying patients most at risk for this complication remains difficult. We aimed to correlate intra-operative physiologic measurements of the lower esophageal sphincter (LES) at the gastroesophageal junction (GEJ) during robotic sleeve gastrectomy in an attempt to identify predictors of post-sleeve GERD symptoms. METHODS: A retrospective chart review of a prospectively maintained database identified 28 patients in whom robotic sleeve gastrectomy was performed utilizing EndoFLIP™ technology between January and September 2021. Intraoperative LES measurements at the GEJ including cross-sectional area (CSA), distensibility index (DI), intra-balloon pressure, and high-pressure zone (HPZ length) were correlated with post-operative GERD. RESULTS: GEJ CSA, pressure, and DI increased over the course of the surgery (CSA pre-op: 31 (IQR 19.3-39.5) mm2 vs. post-op: 67 (IQR 40.8-95.8) mm2, p < 0.001; pressure: 25.8 (IQR 20.2-33.1) mmHg vs. 31.5 (IQR 28.9-37.0) mmHg, p = 0.007; DI 1.1 (IQR 0.8-1.8) mm2/mmHg vs. 2.0 (IQR 1.2-3.0) mm2/mmHg, p = < 0.001), whereas HPZ length decreased (2.5 (IQR 2.5-3) cm vs. 2.0 (IQR 1.3-2.5) cm, p = 0.022). Twenty-three patients (82.1%) completed a post-operative GERD questionnaire. Fifteen (65.2%) had no GERD symptoms before or after surgery; 5 (21.7%) reported new post-sleeve GERD symptoms; 3 (13.0%) reported exacerbation of pre-existing GERD symptoms. Patients with new or worsening GERD symptoms had higher post-sleeve DIs (3.2 (IQR 1.9-4.5) mm2/mmHg vs. 1.5 (IQR 1.2-2.4) mm2/mmHg, p = 0.024) and lower post-sleeve LES pressures (29.9 (IQR 26.3-32.9) mmHg vs. 35.2 (IQR 31.0-38.0) mmHg, p = 0.023) than those without. CONCLUSIONS: An increase in GEJ CSA, pressure, and DI, and a decrease in GEJ length can be expected during robotic sleeve gastrectomy. Patients with new or worsening post-sleeve GERD symptoms have higher post-sleeve DI and lower post-sleeve LES pressure than their asymptomatic counterparts.

Quantifying physiologic parameters of the gastroesophageal junction during re-operative anti-reflux surgery.

BACKGROUND: Hiatal hernia re-approximation during index anti-reflux surgery (ARS) contributes approximately 80% of overall change in distensibility index (DI) and, potentially, compliance of the gastroesophageal (GEJ), while sphincter augmentation contributes approximately 20%. Whether this is seen in re-operative ARS is unclear. We quantify the physiologic parameters of the GEJ at each step of robotic re-operative ARS and compare these to index ARS. METHODS: Robotic ARS with hiatal hernia repair was performed on 195 consecutive patients with pathologic reflux utilizing EndoFLIP™, of which 26 previously had ARS. Intra-operative GEJ measurements, including cross-sectional area (CSA), pressure, DI, and high-pressure zone (HPZ) length were collected pre-repair, post-diaphragmatic re-approximation, post-mesh placement, and post-lower-esophageal sphincter (LES) augmentation. RESULTS: Both cohorts were similar by sex and BMI and underwent similar procedures. The re-operative cohort was older (60.6 ± 15.3 vs. 52.7 ± 16.2 years, p = 0.03), had more frequent pre-operative dysphagia (69.2% vs. 42.6%, p = 0.01) and esophageal dysmotility on barium swallow (75.0% vs. 35.0%, p < 0.001) but lower rates of hiatal hernia on endoscopy (30.8% vs. 68.7%, p < 0.001) compared to index procedures. Among the re-operative cohort, the CSA decreased by 34 (IQR - 80, - 15) mm2 and DI 1.1 (IQR - 2.4, - 0.6) mm2/mmHg (both p < 0.001). Pressure increased by 11.2 (IQR 4.7, 14.9) mmHg and HPZ by 1.5 (1,2) cm (both p < 0.001). These changes were similar to those seen in index ARS. Diaphragmatic re-approximation contributed to a greater percentage of overall change to the GEJ than did the augmentation procedure, with 72% of the change in DI occurring during hiatal closure, similar to that seen during index ARS. CONCLUSIONS: During re-operative ARS, dynamic intra-operative monitoring can quantify the effects of each operative step on GEJ physiologic parameters. Diaphragmatic re-approximation appears to have a greater effect on GEJ physiology than does LES-sphincter augmentation during both index and re-operative ARS.

Evaluation of post-operative dysphagia following anti-reflux surgery.

BACKGROUND: Anti-reflux surgery (ARS) has known long-term complications, including dysphagia, bloat, and flatulence, among others. The factors affecting the development of post-operative dysphagia are poorly understood. We investigated the correlation of intra-operative esophagogastric junction (EGJ) characteristics and procedure type with post-operative dysphagia following ARS. METHODS: Robotic ARS was performed on 197 consecutive patients with pathologic reflux utilizing EndoFLIP™ technology. Intraoperative EGJ measurements including distensibility index (DI), cross-sectional area (CSA), and high-pressure zone (HPZ) length were collected. Dysphagia was assessed pre-operatively and at 3 months post-operatively. RESULTS: The median pre-operative DI for all procedures was 2.6 (IQR 1.6-4.5) mm2/mmHg. There was no difference in post-operative DI between procedures [Hill: 0.9 (IQR 0.7-1.1) mm2/mmHg, Nissen: 1.0 (IQR 0.7-1.4) mm2/mmHg, Toupet: 1.2 (IQR 0.8-1.5) mm2/mmHg, Linx: 1.0 (IQR 0.7-1.2) mm2/mmHg, p = 0.24], whereas post-operative HPZ length differed by augmentation type [Hill: 3 (IQR 2.8-3) cm, Nissen: 3.5 (IQR 3-3.5) cm, Toupet: 3 (IQR 2.5-3.5) cm, Linx: 2.5 (IQR 2.5-3) cm, p = 0.032]. Eighty-nine patients (45.2%) had pre-operative dysphagia. Thirty-two patients (27.6%) reported any dysphagia at their 3-month post-operative visit and 12 (10.3%) developed new or worsening post-operative dysphagia [Hill: 2/18 (11.1%), Nissen: 2/35 (5.7%), Toupet: 4/54 (7.4%), Linx: 4/9 (44.4%), p = 0.006]. The median pre-operative and post-operative DI of patients who developed new or worsening dysphagia was 2.0 (IQR 0.9-3.8) mm2/mmHg and 1.2 (IQR 1.0-1.8) mm2/mmHg, respectively, and that of those who did not was 2.5 (IQR 1.6-4.0) mm2/mmHg and 1.0 (IQR 0.7-1.4) mm2/mmHg (p = 0.21 and 0.16, respectively). CONCLUSIONS: Post-operative DI was similar between procedures, and there was no correlation with new or worsening post-operative dysphagia. Linx placement was associated with higher rates of new or worsening post-operative dysphagia despite a shorter post-procedure HPZ length and similar post-operative DI when compared to other methods of LES augmentation.

Why do some promising brain-stimulation devices fail the next steps of clinical development?

Interest in techniques of noninvasive brain stimulation (NIBS) has been growing exponentially in the last decade. Recent studies have shown that some of these techniques induce significant neurophysiological and clinical effects. Although recent results are promising, there are several techniques that have been abandoned despite positive initial results. In this study, we performed a systematic review to identify NIBS methods with promising preliminary clinical results that were not fully developed and adopted into clinical practice, and discuss its clinical, research and device characteristics. We identified five devices (transmeatal cochlear laser stimulation, transcranial micropolarization, transcranial electrostimulation, cranial electric stimulation and stimulation with weak electromagnetic fields) and compared them with two established NIBS devices (transcranial magnetic stimulation and transcranial direct current stimulation) and with well-known drugs used in neuropsychiatry (pramipexole and escitalopram) in order to understand the reasons why they failed to reach clinical practice and further steps of research development. Finally, we also discuss novel NIBS devices that have recently showed promising results: brain ultrasound and transcranial high-frequency random noise stimulation. Our results show that some of the reasons for the failure of NIBS devices with promising clinical findings are the difficulty to disseminate results, lack of controlled studies, duration of research development, mixed results and lack of standardization.